European Heart Journal (2011) 32, 1673–1686
doi:10.1093/eurheartj/ehr171
ESC REPORT
Clinical evaluation of cardiovascular devices:
principles, problems, and proposals for
European regulatory reform
Report of a policy conference of the European Society of Cardiology†
Alan G. Fraser *, Jean-Claude Daubert, Frans Van de Werf, N.A. Mark Estes III,
Sidney C. Smith Jr, Mitchell W. Krucoff, Panos E. Vardas, and Michel Komajda,
on behalf of the participants‡
Department of European Affairs, European Society of Cardiology, The European Heart House, 2035 Route des Colles – Les Templiers, 06903 Sophia Antipolis, France
Received 11 April 2011; accepted 6 May 2011; online publish-ahead-of-print 14 May 2011
The European Commission announced in 2008 that a fundamental revision of the medical device directives is being considered in order to
clarify and strengthen the current legal framework. The system for testing and approving devices in Europe was established .20 years ago as
a ‘New Approach’ to a previously little-regulated industry. It is recognized by many that the regulatory system has not kept pace with technological advances and changing patterns of medical practice. New legislation will be drafted during 2011, but medical experts have been little
involved in this important process. This context makes it an opportune time for a professional association to advise from both clinical and
academic perspectives about changes which should be made to improve the safety and efficacy of devices used in clinical practice and to
develop more appropriate systems for their clinical evaluation and post-marketing surveillance. This report summarizes how medical
devices are regulated and it reviews some serious clinical problems that have occurred with cardiovascular devices. Finally, it presents
the main recommendations from a Policy Conference on the Clinical Evaluation of Cardiovascular Devices that was held at the European
Heart House in January 2011.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Medical devices † European device directives † Recast of legislation † Premarket approval † Post-marketing
surveillance
Introduction
A medical device is defined as ‘any instrument, apparatus, appliance, software, material or other article, whether used alone or
in combination, together with any accessories, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper
application, intended by the manufacturer to be used for human
beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease..’.1
The use and complexity of diagnostic and therapeutic devices is
increasing, particularly in cardiovascular medicine, and expenditure
on devices contributes significantly to the escalating costs of health
care. The medical device sector in Europe has grown to .11 000
companies, which employ more than half a million people and have
†
This report presents a summary and the consensus conclusions from the Policy Conference organized by the European Society of Cardiology (ESC) and held at the European Heart
House on 27 –28 January 2011. It does not necessarily reflect the opinions of individual participants.
* Corresponding author: Tel: +33 4 9294 8662, Email: [email protected]
‡
The list of participants are given in the appendix section. Anker SD, Auricchio A, Bailey S, Bonhoeffer P, Borggrefe M, Brodin L-Å, Bruining N, Buser P, Butchart E, Calle Gordo J,
Cleland J, Danchin N, Daubert JC, Degertekin M, Demade I, Denjoy N, Derumeaux G, Di Mario C, Dickstein K, Dudek D, Estes NA, Farb A, Flotats A, Fraser AG, Gueret P, Israel C,
James S, Kautzner J, Komajda M, Krucoff MW, Lombardi M, Marwick T, Mioulet M, O’Kelly S, Perrone-Filardi P, Rosano G, Rosenhek R, Sabate M, Smith SC, Swahn E, Tavazzi L, Van
de Werf F, van der Velde E, van Herwerden L, Vardas PE, Voigt J-U, Weaver D and Wilmshurst P.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]
1674
combined annual sales of .E72 billion.2 Estimates of the total
number of medical devices range upwards from 200 000. There
is a clear need for safety and performance to be established
before new medical devices are approved but there is a fundamental tension between providing high-level clinical evidence and promoting innovation. Rational practice with minimal inappropriate
use is in the interests of patients and providers, and clinical
safety must come first.
It can be argued that the manufacturers of devices used in medicine have the same ethical responsibilities to the individual patient,
as have those companies which manufacture and sell drugs. Many
principles of regulatory approval are similar—such as an evaluation
of risks and benefits—but the processes by which devices and
drugs are governed within Europe vary greatly.
The European Medicines Agency (EMA) was established in 1995.
Its main responsibility is the protection of public health through the
scientific evaluation and supervision of medicines. Companies can
submit a single application to the EMA for authorization by the
European Commission (EC) and marketing throughout Europe.
The Committee for Medicinal Products for Human Use is responsible for conducting the initial assessment of medicines for which
an European Union (EU)-wide marketing authorization is sought;
it has a Cardiovascular Working Party. The EMA is also responsible
for pharmacovigilance and for coordinating national authorities. It
works with a network of .4500 European experts. In general,
proof of safety and clinical efficacy is required from randomized
trials before a new drug can be introduced. The manufacturer of
a generic version of an existing drug must produce a virtually identical compound ‘with the same qualitative and quantitative composition in active substance(s)’, ‘the same pharmaceutical form’, and
demonstrated ‘bioequivalence to the reference product’,3 before
it can be marketed.
The regulation of medical devices is the responsibility of the 27
Member States of the EU, each of which has its own national ‘competent authority’. Many national authorities have combined
responsibilities for overseeing both drugs and devices, but there
is no single, common European agency for assessing devices; the
main role of the EC is advisory. For approval, manufacturers
must satisfy the relevant ‘essential requirements’ of safety and performance but they do not always need to establish that their
medical device has an impact on clinical outcomes, even if it is a
completely new technology. If an equivalent device does exist,
then a new device once approved can be marketed as an alternative without the manufacturer being required to prove in
head-to-head comparisons that its clinical effectiveness is similar.
The system for testing and approving devices in Europe was
established .20 years ago as a ‘New Approach’ to a previously
little-regulated industry. It is recognized by many that the regulatory system has not kept pace with technological advances and
changing patterns of medical practice. In 2008, the EC announced
that a fundamental revision is being considered,4 in order to clarify
and strengthen the current legal framework. Producing one
common document from many existing texts will also simplify
the legislation and meet a commitment of the Treaty of Lisbon
which came into force in December 2009. The recast will be a
joint decision for the Council of Ministers and the European
Parliament, on the basis of a proposal adopted by the College of
A.G. Fraser et al.
Commissioners and drafted by the Cosmetics and Medical
Devices Unit of the EC, which moved in 2010 from being part
of the Directorate General for Enterprise and Industry (DG
ENTR) to the Directorate General for Health and Consumer
Affairs (DG SANCO).
This context makes it an opportune time for the medical profession to advise from both clinical and academic perspectives
about changes which should be made to improve the safety and
efficacy of devices used in clinical practice and to develop more
appropriate systems for their clinical evaluation and post-marketing
surveillance (PMS).
Background: current regulations
European Union
Rules relating to the safety and performance of medical devices
were harmonized in the EU in the 1990s, with the adoption of
directives concerning Active Implantable Medical Devices
(1990),5 other Medical Devices (1993),6 and In Vitro Diagnostic
Medical Devices (1998).7 These three main directives have been
transposed into the national laws of EU Member States. After
the EC decided in 2005 that the medical device directives
needed revision,8 they were supplemented in 2007 by a modifying
directive which introduced new essential requirements and recommendations concerning clinical evaluation and vigilance,1 and
in 2009 by an amendment concerning common technical specifications for in vitro diagnostic medical devices.9 This main legal framework is complemented by non-binding guidance (called MEDDEV
documents)10 – 12 including consensus statements and interpretative documents which aim to ensure uniform application of the
relevant provisions of the directives within the EU. The system is
shared by another five countries in the European Economic Area
(EEA) and the European Free Trade Association (EFTA) with
which the EC has signed a free trade agreement.
Devices are assigned to four groups according to risk13 and
these relate to different levels of testing and evidence that are
needed before they are approved. For low-risk cardiovascular
devices in Class I, ranging from stethoscopes to cooling jackets
for patients who have suffered a cardiac arrest, generally little
evaluation is needed before the device is placed on the market;
the manufacturer is allowed to self-declare conformity with the
essential requirements, affix a CE mark, and register its product
with a competent authority. Class IIa includes devices for monitoring blood pressure, and diagnostic equipment for magnetic resonance imaging, ultrasound scanning, and nuclear studies using
gamma cameras or positron emission tomography. Class IIb
includes other diagnostic radiology equipment such as X-ray
machines. Class III, the highest risk group, includes invasive or
implantable devices such as coronary stents, prosthetic heart
valves, pacemakers, implantable defibrillators, and devices and
leads for resynchronization therapy.
Any manufacturer wishing to obtain approval to market a new
device in a medium- or high-risk group (classes IIa, IIb, III)13 must
undergo a ‘conformity assessment procedure’ involving one or
more Notified Bodies (NBs). The manufacturer must demonstrate
safety and conformity with the legal requirements contained in the
Clinical evaluation of cardiovascular devices
first annexes of the three directives. To do this, the manufacturer
may refer to relevant technical standards such as those from the
European Committee for Standardization (CEN) and the European
Committee for Electrotechnical Standardization (CENELEC).14 In
most instances, these mirror the standards from the International
Organization for Standardization (ISO) and the International Electrotechnical Commission (IEC). Effective performance of the
device for its intended purpose (as claimed by the manufacturer)
needs to be demonstrated. The precise definition of the designated
task of any device, therefore, is a key decision for each manufacturer. It can be argued that this process encourages the manufacturer to keep its claims for a device as simple as possible.
The clinical data used for CE marking may be a critical evaluation
of the relevant scientific literature currently available relating to the
design characteristics, intended purpose, safety, and performance
of a device, when it is demonstrated to be equivalent to another
device which already complies with relevant essential requirements
and for which there are data. Alternatively, the manufacturer may
present a critical evaluation of the results of all reported clinical
investigations that have addressed residual safety concerns.10,15
For devices in Class III, the manufacturer must conduct some
human clinical investigations, but it is not compulsory that these
are randomized clinical trials.
Notified Bodies
A medical device company is free to approach any NB in Europe
that has been designated for the respective ‘conformity assessment
procedure’ (Figure 1). This process has given rise to suspicions that
companies may go ‘forum shopping’ to select the NB that will
conduct the least burdensome or the fastest review, but no systematic audit of the NBs has been published. Since 1985, a NB
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has been any organization designated to assess if manufactured
products conform with the requirements of any EU new approach
directive; the website of the Enterprise and Industry DirectorateGeneral listed 2271 NBs in January 2011. Of these, 74 were
approved to evaluate medical devices, including some organizations located outside the EU;16 several NBs have been approved
to evaluate all medical devices. Most NBs are independent commercial organizations, and they are supported in part by the fees
paid by device companies. Notified Bodies are designated, monitored, and audited by the competent authorities of the member
state in which they are based.
The duties of a NB are to review the technical dossier submitted
by the manufacturer, to assess the manufacturer’s quality management system, and to evaluate any evidence that has been submitted
from laboratory, animal, and clinical studies. The manufacturer
submits a sample of the device under review, and the NB may
conduct direct testing especially if it is an active medical device.
The NB may also visit the manufacturer to inspect the production
process and quality control. If these tests are judged satisfactory,
then the NB issues a certificate (which is valid for a maximum of
5 years before renewal) and the manufacturer can affix the
CE mark (Figure 1). Thereafter, the device can be marketed
throughout the EU.
Some NBs also function as national standards institutes and their
division with this responsibility may participate in writing ISO standards. In addition, national competent authorities have specified
that NBs, as part of their contract, should participate in the vigilance (or PMS) of medical devices, in which case they receive
reports of adverse incidents. Reports are also transmitted together
with the proposed ‘Field Safety Corrective Action’ (FSCA) by the
manufacturer to the competent authority which is responsible for
Figure 1 Summary of the major steps in the current regulatory framework for approving medical devices in Europe. Solid lines denote formal
requirements; dotted lines represent guidance or advice. DG SANCO ¼ Directorate General for Health and Consumer Affairs.
1676
their review. If a device needs to be removed from the market, it is
the responsibility of the NB to suspend its certificate.
Coordination
The Committee on Medical Devices, organized by the EC and
composed of representatives of the Member States, has specific
regulatory powers for the device directives. Policy is coordinated
by the Medical Devices Experts Group (MDEG) which is said to
‘encompass all stakeholders’.17 Its members include representatives from trade federations, CEN, CENELEC, NBs, and patients’
organizations. There are currently no members from European
medical associations, although the EC states that they have previously been invited.
The Notified Bodies group (NB-MED) and the Notified Bodies
Operation Group (NBOG) were established by the EC to improve
cooperation and performance of the NBs with the competent
authorities in the medical devices sector.
The European Databank on Medical Devices (Eudamed) was
created in 1998 to allow Member States to strengthen PMS by
exchanging information about adverse events related to the use
of medical devices. Reporting will become mandatory from May
2011.18 Competent authorities will have rapid access to the database which will include names of registered manufacturers, data
relating to certificates, and reports from vigilance procedures
with the findings of clinical investigations. The European Databank
on Medical Devices will implement the Global Medical Device
Nomenclature (GMDN) code; there is also a GMDN Agency,
established under the auspices of CEN. There is no plan to open
the contents of Eudamed to the public.
The USA
In the USA, the evaluation and approval of medical devices is the
responsibility of the Food and Drug Administration (FDA)
through its Center for Devices and Radiological Health (CDRH),
which has a Division of Cardiovascular Devices. As in Europe,
devices are categorized by risk into three classes, and higher
levels of evidence including clinical evidence are required for
approval of devices in Class III. In addition to internal regulatory
review by FDA personnel, advice is often sought from external,
independent experts through well-established Medical Devices
Advisory Committees (including a Circulatory System Devices
Advisory Panel),19 for example, for first-of-a-kind devices and for
devices that are expected to have a broad impact on public
health. This provides a transparent mechanism for public review
of issues relating to the approval of complex devices.
Low-risk devices (class I) are approved by registration, after
compliance with general controls such as regulations for good
manufacturing practice. More complex, moderate-risk devices
(class II) require additional special controls, such as specific labelling, compliance with requirements in guidance documents,
device tracking, and design controls. The regulatory pathway for
class II products is through the Premarket Notification [‘510(k)’]
programme, which is the pathway through which most medical
devices are marketed. A manufacturer submits a ‘premarket notification’ asserting that their new device is substantially equivalent
(i.e. at least as safe and effective) as one (‘the predicate’) that is
already legally on the market. If the FDA determines that the
A.G. Fraser et al.
information and performance testing demonstrate that this is the
case, then the device can be marketed in the USA. Ten to 15%
of 510(k) submissions require data from human clinical studies to
supplement preclinical testing.
High-risk devices (class III) follow the regulatory pathway for
premarket approval (PMA). This requires a comprehensive evaluation including bench testing, preclinical animal studies, and clinical
data, so that the device demonstrates a reasonable assurance of
safety and effectiveness. The term ‘effectiveness’ means that the
device will provide clinically significant benefits, and thus evaluation
focuses on clinical outcomes such as a reduction in symptoms or
adverse events. In contrast, ‘performance’ (a standard EU regulatory parameter) focuses on a device’s mechanism of action such as
enlargement of the arterial lumen or enhanced myocardial blood
flow. Clinical data for a PMA are typically obtained from feasibility
studies followed by a larger, ‘pivotal’ trial. In order to conduct a
clinical trial in the USA to assess the safety and effectiveness of a
‘significant risk’ device and thereby provide evidence that will
support a PMA or 510(k), the sponsor must obtain FDA approval
of an Investigational Device Exemption (IDE).
In general, regulatory reviews by the FDA incorporate more
detailed technical standards and requirements for clinical evaluation of devices than occurs in Europe, and they are more rigorous.
Preclinical testing plays a more important role, with questions
regarding long-term durability and local and systemic histopathological responses being addressed in bench and animal studies. Since
the FDA requires adequate preclinical safety data before the
initiation of human trials, there may be a lag of several years
after the introduction of some devices for clinical use within
Europe before they are used in patients in the USA. Many US companies first get approval for their new medical devices in the EU
and then use ‘OUS’ (outside the USA) data relating to safety and
effectiveness to support the initiation of a pivotal IDE study at
US study sites.
In a recent decision, the US Supreme Court judged that the
manufacturer of a medical device could not be sued by a patient
on the basis of alleged defects relating to its safety because the
device had received PMA from the FDA.20 The consequences of
this decision are still unclear; for example, it is uncertain if it may
encourage manufacturers to submit more detailed claims for
devices when applying for regulatory approval.
For permanently implanted class III devices such as coronary
stents and devices for occluding intracardiac shunts, the FDA typically requires 5 years of clinical follow-up. Post-approval clinical
studies that collect and report real-world outcomes associated
with the use of novel devices are also commonly required. The
FDA has had a policy of ‘global transparency’ since 1994 and all
medical device reports (MDRs) concerning significant adverse
events are available on the Internet.
United States and OUS device manufacturers can meet with
FDA staff at multiple times during the development of a device,
through the CDRH’s Pre-Submission Program. These informal
meetings are particularly useful for the sponsors and the FDA to
reach consensus on preclinical device testing, key elements of
IDE clinical trials, and requirements for PMA submissions. The
510(k) program has been reviewed by the Institute of Medicine21
and it is being reviewed by the FDA. Recommendations which
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Clinical evaluation of cardiovascular devices
will aim to raise standards by incorporating more scientific advice
and objective appraisal are expected in the near future.22
International comparisons
The clinical safety and efficacy of a medical device is less likely to
vary between countries when it is used for the same indication
in patients with the same condition, than may occur with drugs
that are metabolized, but it may be affected by the experience
of the physician. Nonetheless, from a clinical perspective, substantial variations in requirements for its approval may be illogical.
Although there is no international legal basis for coordinating the
scrutiny of medical devices, a voluntary collaboration between
the national regulatory authorities in Europe, Japan, Australia, the
USA, and Canada was established in 1992, called the Global Harmonization Task Force (GHTF). Its objective is to share experience
between competent authorities of their varying approaches to the
regulation and control of medical devices and to encourage convergence towards common essential principles of their evaluation.
The GHTF has a study group on clinical safety and performance
which has published recommendations concerning clinical evaluation (2007),23 clinical investigation of devices before approval
(2010),24 and clinical follow-up studies (2010).25 The vice-chair
of each GHTF committee has come from industry.
The organization and membership of the GHTF are being
reviewed.26 It has been noted that uniform implementation of
the recommended common models of governance has not been
achieved. Since a meeting in February 2011, the regulators have
announced that they will seek a regulator-led group with the
task of increasing coordination and harmonization. Not just industry, but healthcare professional groups, academics, and consumers
will be consulted as appropriate.
Two other international collaborations of regulatory authorities,
the Asian Harmonization Working Party (AHWP) whose .20
members include China and India, and the Latin American Harmonization Working Party (LAHWP), work in conjunction with the GHTF.
The Technical Committees of ISO produce international standards for medical devices.27 TC210 on quality management is
coordinating its work with the GHTF. TC194 (biological evaluation
of medical devices) publishes ISO Standard 14 155 concerning
clinical investigations of medical devices.28
Whether or not a device is used or its use is reimbursed after its
safety, and clinical performance or efficacy, have been established,
depends on national health-care systems and varies according to
local circumstances. Availability may be influenced by decisions
taken by national bodies responsible for health technology assessment; 34 such agencies from countries within the EU, EEA, and
EFTA, collaborate through the European Network for Health
Technology Assessment (EUnetHTA) to share knowledge and
promote good practice in their methods and processes.29 There
is overlap between these bodies and the regulatory authorities,
since the core model for health technology assessment lists criteria
that include safety and clinical effectiveness.30
The World Health Organization has published two important
papers concerning medical devices—a global overview of regulations, in 2003,31 and most recently, in 2010, a call for improving
access to medical devices in poorer nations.32 The common framework for medical device regulations mentions safety, performance,
and vigilance, but not clinical trials.31 In 2007, the World Health
Assembly noted the need to expand expertise in medical devices,
and it called for regional guidelines on regulatory practices ‘to
ensure the quality, safety and efficacy of medical devices and
where appropriate participation in international harmonization’.33
It organized the first global forum on medical devices, in 2010. The
strategic plan of WHO includes the objective ‘to ensure improved
access, quality and use of medical products and technologies.’34
Europe, the USA and Japan account for 89% of the world market
for medical devices.2 This is likely to change, but at present,
countries with minimal resources to purchase devices probably
have similarly scarce resources to evaluate them. Proper evaluation
could reasonably be a responsibility of those countries with a disproportionate share per capita of the use of devices. One of the
four principles of the current EU strategy for health is to offer
‘sustained collective leadership in global health . . . by sharing its
values, experience and expertise . . . ’.35
Lessons from clinical experience
Medical devices have been hugely beneficial for countless patients,
but some well-publicized failures of cardiovascular devices causing
clinical problems have prompted concerns about the adequacy of
current standards for evaluation before approval. There have also
been examples of the rapid clinical uptake of devices that were
later proved to be ineffective or harmful. Examples are discussed
below, and possible contributory factors relating to regulatory processes are listed in Table 1.
Heart valves
In 1980 (before the European device directives were adopted),
Shiley, Inc., modified their Björk– Shiley Convexo– Concave heart
valve by increasing its opening angle to 708. The valve was withdrawn in 1983 after catastrophic failures had been observed that
were caused by spontaneous fracture of the outlet strut that
held the occluder in place.36,37 The increased risk was at least
three-fold, compared with the previous design,36 and the absolute
risk was 0.7%.38 Detailed investigations traced the cause back to
a change in the manufacturing process. Similar valve failure had
occurred during the premarket trial of the valve but permission
was given by the FDA for the valve to be exported from the US
manufacturing site, as the first valve failure was believed to be an
isolated case39 and other available data suggested that it was safe
and effective. Subsequently, mortality rates in patients with strut
fracture of up to 84%40 led to recommendations for patients in
high-risk groups to undergo elective explantation and
re-replacement.40,41 In retrospect, prolonged accelerated wear
testing of the valve in a pulse duplicator might have revealed the
problem, because detailed examination of explanted valves
showed serious prefracture defects in 32% that increased with
the duration of implantation.42 In the USA, the 708 valve was
never approved by the FDA, and the 608 Convexo –Concave
valve which had received FDA approval was withdrawn also due
to strut fracture.
In 1997, the St Jude heart valve was modified by impregnating its
sewing ring with silver, which has antibacterial properties in vitro.
The new model of this valve, called the Silzone valve, was taken
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Table 1 Some lessons learned from clinical
experience of cardiovascular devices
Heart valves
Animal models dissimilar from human, insufficiently predictive45
Inadequate bench testing of mechanical properties36,42
Incomplete assessment of fluid mechanical properties47,48
Approval of changes as iterative that proved to be
substantial36,39,43,44
A.G. Fraser et al.
Gersh et al.49 identified the need for common standards for
evaluating heart valves and subsequent authors suggested alternatives to randomized trials.50,51 In 1994 the FDA responded by
issuing ‘objective performance criteria’ for heart valves.52 More
recently, experts have revised recommendations for the evaluation
of valve performance and the reporting of complications.53 Recommendations for reporting endpoints in clinical trials of transcatheter aortic valve implantation (TAVI) have also been
published54 and endorsed by the FDA.55
................................................................................
Percutaneous coronary interventions
Clinical application of concept that was not proved60,66,80
Use of unblinded studies with significant placebo effect80
Over-reliance on composite end-points71
Overuse of equivalence for CE marking without new pivotal
trials57 – 60
Devices not taken off market when negative long-term outcome
trials reported65,81
................................................................................
Diagnostic imaging
No standard industry-wide phantoms for some imaging modalities
No reporting of diagnostic accuracy and reproducibility by
manufacturers
No requirements for manufacturers to present normal values
................................................................................
Cardiovascular implantable electronic devices
Need for long-term registries conducted independently from
industry106,118
Incomplete capture of clinical events by registries with voluntary
reporting
Need for rapid and open access to reports of device failures110,111
................................................................................
Closure of patent foramen ovale
Early CE marking leading to rapid adoption before proven clinical
benefit
Failure by physicians to enrol patients in trials124,125
off the market after the AVERT trial reported paraprosthetic
regurgitation in 8.9% of patients at 2 years, compared with 1.1%
in patients receiving the standard model.43 The Silzone valve was
also associated with a high incidence of valve thrombosis and
thromboembolism.43,44 It has since been recognized that toxic biological properties of silver prevented normal tissue ingrowth and
endothelialization of the sewing ring, but this problem had not
been revealed by reports from a small preliminary animal
study.45 At the time of its recall, the manufacturer estimated that
36 000 Silzone valves had already been implanted.46
In these cases, changes to the design of a valve had been
approved without evidence from prospective clinical trials, on
the basis that they were minor modifications. A third mechanical
prosthesis, the Medtronic Parallel valve, was also withdrawn from
the market after early incidents of thrombosis, in this case
related to pockets of stasis. Valve thrombosis might have been predicted by fluid dynamic computational simulations and in vitro
studies,47,48 before human implants, but the patterns of retrograde
flow through the hinge pockets had not been studied. The Parallel
valve was neither studied nor approved in the USA; it was evaluated in 16 European centres.
Percutaneous interventions for coronary
artery disease
The initial success rate of balloon coronary angioplasty was 63%,
and the procedure was first approved by the FDA after 60 patients
had been treated for 6 months.56 In early series, .10% of patients
required emergency bypass surgery and there were many deaths. It
would have been very difficult to get such approval, either in the
USA or in Europe, if angioplasty had had to be tested against
surgery while the technology was in its infancy. Early approval
gave an impetus to technological developments in interventional
cardiology and to many important randomized clinical trials in
Europe, resulting in a highly effective treatment that reduces morbidity and mortality.57 Nonetheless, several scores of coronary
stents have received a CE mark and are available within Europe,
in spite of the fact that only six drug-eluting stents have been
proved to be effective by meeting primary clinical endpoints in
pivotal trials.57 Long-term results (≥5 years) are available for
only three stents.57 It has been recommended that market
access should be based on efficacy58 but many stents have been
approved on the basis of technical equivalence rather than clinical
outcomes. In some countries, reimbursement is limited to proved
devices but in others, doctors may be asked to use cheaper stents
even when proof is lacking.
It cannot be assumed that either bare metal or drug-eluting
stents are all similar.58,59 For example, the Niroyal stent was
gold plated in order to enhance its opacity on radiographic screening. It was given a CE mark in May 1999 without a pre-marketing
clinical trial. A registry reported in 2000 that it gave excellent
primary angiographic success rates, and event rates at 6 months
were lower than reported in other series.60 A randomized trial,
however, showed a smaller minimal luminal diameter and a
higher late loss.61 The adverse effects of gold plating were confirmed independently by other investigators.62
Directional coronary atherectomy was evaluated between 1988
and 1990 under an IDE. The device was approved by the FDA in
September 1990 on the basis of a primary success rate of 85%,
although one or more major complications occurred in 4.9% of
procedures and the restenosis rate at 6 months was 42%.63 In
the CAVEAT study, the new technique had a higher rate of early
complications (11%) and it conferred no significant benefit over
balloon angioplasty alone at 6 months.64 One-year follow-up
revealed an increase in mortality at 2.2% in the atherectomy
group compared with 0.6% in controls.65 The device was withdrawn from the market for commercial reasons rather than
because of regulatory decisions. An estimated 177 000 patients
were treated worldwide.66
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Clinical evaluation of cardiovascular devices
The first clinical use of intracoronary beta or gamma irradiation
(brachytherapy) to prevent or treat restenosis after balloon angioplasty was reported from a Swiss pilot study of 15 patients in
1997.67 The investigators obtained informed consent from their
patients after the protocol had been approved by the hospital
Ethics Committee, but there is no reference in their manuscript
to regulatory issues or approval for use of a prototype device.
A similar clinical pilot study of 23 patients was reported from
the USA in 1998 by investigators who had obtained an IDE.68 In
early clinical trials, brachytherapy was reported to reduce restenosis within a stent but it increased stenosis at the stent margins by
up to four-fold.69,70 After two more trials71,72 the FDA approved
brachytherapy in 2001 for the treatment of in-stent restenosis,
but with conditions because of reports of thrombosis particularly
when anti-platelet treatment was discontinued.73 By this time,
small animal models had already revealed incomplete healing
with poor endothelialization74 and edge effects.75 A registry of
1098 patients from 46 centres reported good results and
showed considerable adoption of the new technique in
Europe.76 Further randomized controlled trials, however, confirmed that both the early and late results of brachytherapy
were worse than standard therapy77 or therapy with drug-eluting
stents.78,79 This discrepancy between registries and randomized
trials highlights the importance of independent PMS studies with
centrally adjudicated and monitored adverse events.
The rationale proposed for laser myocardial revascularization
was that creating multiple pits in ischaemic myocardium with a
laser beam would promote the formation of collateral channels
or new vessels. The concept was developed as a surgical technique
and evolved towards percutaneous delivery. In an initial unblinded
trial, 221 patients were randomized to laser or continued medical
treatment.80 Patients treated with laser revascularization had
improved exercise tolerance at follow-up but more deaths than
controls. The technique was used in a limited number of centres,
mainly because of its cost, until a later blinded trial of 298 patients
in which controls underwent a sham procedure, showed no functional benefit and increased early complications in laser-treated
patients.81 Percutaneous laser revascularization was not approved
by the FDA. Recent UK guidance concluded that it was ineffective,
had unacceptable risks, and should not be used.82 Some laser
systems are still commercially available, however, and occasionally
used during surgery.
When detailed professional recommendations are produced,
there is some evidence that these are taken up by regulators.
The 2007 report of the Academic Research Consortium on clinical
endpoints in coronary stent trials83 was cited in regulatory guidance published by the EC in 2008.84 An earlier expert document85 and a more recent consensus conference on drug-eluting
stents, both organized by the ESC, had no official status but established a useful model of dialogue between clinical investigators,
regulators, and industry.58 It was recommended that the EC
should produce uniform standards in a guidance document58 but
this has not yet been done, perhaps because the EC does not
have the authority or responsibility to commission such standards.
Recent authors have advocated a balance between the more
detailed assessment conducted by the FDA and the more rapid
response to innovations that is possible in Europe.86
Diagnostic imaging
Medical imaging has the highest growth rate within the health-care
sector (10% per year)87,88 but it may be the least supported by
objective data—for example, only 4.8% of the recommendations
included in guidelines for radionuclide imaging from the American
College of Cardiology and the American Heart Association are
supported by evidence from multiple randomized clinical trials89
although these have been recommended as the desired method
for establishing the clinical efficacy of diagnostic devices.90
The hardware and software used by any company in an imaging
system may be considered as intellectual property and protected
by patents. If another company wishes to offer its customers equivalent diagnostic tools, it must produce its own (quite possibly
unique) solutions to the engineering challenges, including decisions
about how the raw signals are obtained, processed, and smoothed,
as well as how they are displayed. There is a single industry standard for exporting images (digital images and communication in
medicine—DICOM) that is coordinated by the Association of
Electrical and Medical Imaging Equipment Manufacturers (NEMA)
in the USA. DICOM is designed so that images from one
machine can be viewed on other systems, but it has not been
adapted for all new methods (such as real-time acquisition of 3D
images) or fully applied by all manufacturers, and thus complete
interoperability remains elusive.
It is increasingly apparent that detailed measurements obtained
using the diagnostic equipment of one manufacturer may vary substantially from the same measurements obtained in the same
patient by using a similar machine from a different manufacturer91,92
or by using a different imaging modality for the same purpose.93 – 97 In
the PROSPECT trial, echocardiography was used to try to identify
responders to cardiac resynchronization therapy (CRT); six different
machines and more than six versions of software were used, from six
companies, and the analyses were performed in three core laboratories.98 Although the rationale for the study was logical, the
results were negative, perhaps because of wide inter-centre and
inter-machine variability in measurements.
Calls are now being made for more formal evaluation and regulation of imaging technologies, such as CT scanning99 and magnetic
resonance imaging. There is a need to consider the impact of ionizing radiation, especially when safe alternatives are available;100 if
40-year-old subjects have CT coronary angiography, the risk that
they may develop cancer has been estimated at 1 in 270 for
women and 1 in 600 for men.101 With imaging, the greatest risk
to patients may be inappropriate use by an inexperienced operator. Appropriateness criteria do not fill the gap in evidence
since they represent the consensus view of experts as to which
tests are reasonable for which indications, without guaranteeing
that there is evidence of clinical impact. Evaluation of diagnostic
strategies should compare all the alternative tests for any particular
clinical question.102
Cardiovascular implantable electronic
devices
It was estimated in 2007 that almost 700 000 patients in western and
central Europe had implanted pacemakers, another 90 000 implantable cardioverter-defibrillators (ICDs), and 60 000 CRT.103 Many new
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concepts and devices have been developed in Europe. Advanced and
effective device therapy for arrhythmias and/or heart failure can
transform lives, and reliability of individual devices can be 99%.104
Nonetheless, these advanced technologies still have risks, and electronic devices need to be evaluated and monitored carefully.
Fracture of pacemaker leads and technical failures of pacemakers
are a recognized and accepted complication, and the rate of replacement because of pacemaker malfunction is decreasing.105 Longterm studies are needed to assess chronic lead performance106 but
it is unclear how these will be funded or who should organize
them. Remote telemonitoring is now possible. As with diagnostic
imaging, there may be differences between devices such as CRT
which manufacturers offer as equivalent but which have different
technical specifications or treatment algorithms.
There is less clear evidence that the risk of generator malfunction of an ICD is also declining.107,108 Problems such as battery
depletion104 if unexpected can occasionally result in death attributable to device failure.109 Major clinical, ethical, and legal problems
may arise, as in a case where a young patient died when his ICD
malfunctioned; the unit had not been replaced, and the company
had delayed giving any advice to physicians and patients although
they had known for .2 years that there was a risk of technical
failure.110 More recently, lawsuits have been filed against another
company after it too delayed disclosing information, this time
about lead fractures.111 Failure rates for the Medronic Sprint
Fidelis lead have been estimated at 2.3% at 30 months, or
2.6 times the failure rate of a reference lead, and this fault can
cause inappropriate shocks.112
It is difficult for physicians to know how to respond to advisory
notices issued by companies when technical problems are discovered with a particular device, because the risk associated with
replacement of a potentially faulty ICD device may be higher
than its risk of failure.113 Even replacing faulty leads is associated
with major complications in 7% of patients.114 One recommended
approach is to offer elective replacement to device-dependent
patients when the ‘number needed to replace’ (NNR) is ,250.115
Automatic external defibrillators have been classified as class III
devices because of their similarity to other devices in that class, but
many reports of technical failures have been received by the
FDA.116 A discussion paper proposed two options—either to
reclassify them to class II or to increase the levels of proof and
technical performance and reliability required to be demonstrated
by manufacturers before these devices are approved;117 the Circulatory System Devices Panel of the FDA recently recommended
the second option. Increased PMS has also been advocated118
although this may be difficult given the numbers of devices installed
and their location in public places.
Closure of patent foramen ovale
The first use of a percutaneous device for closing a patent foramen
ovale (PFO) was reported in 1992.119 At least 12 different PFO
closure devices have received CE marking. Risks include pericardial
effusion and tamponade, unsuccessful deployment, incomplete
closure, device migration, thrombosis, and the development of
atrial fibrillation.120,121
Between 1999 and 2002, the FDA approved two PFO occluders
as Humanitarian Use Devices, which means that a device has been
A.G. Fraser et al.
designed to treat a disease that occurs in fewer than 4000 people
in the USA per year. The approved indication was limited to
patients with recurrent cryptogenic stroke who had failed conventional drug therapy. Approval was granted through the regulatory
pathway for Humanitarian Device Exemption (HDE), and it was
based upon clinical experience in ,100 patients with each
device. After approval of the HDEs, it became apparent that
many PFO occluders were being implanted off-label for patients
with a first cryptogenic stroke who had not failed medical
therapy. Enrolment in randomized IDE trials comparing device
closure with medical therapy was exceedingly slow. A systematic
review published in 2004 reconfirmed the need for randomized
studies,122 but recruitment continued to lag because ‘some physicians have concluded that the therapy is effective despite the
lack of appropriate evidence’.123 A re-analysis demonstrated that
there were .4000 patients with cryptogenic stroke per year
who might be candidates for PFO closure, and the two industry
sponsors voluntarily withdraw their HDEs in 2006. Enrolment in
studies remained slow despite more recommendations from
FDA Advisory Panels and experts regarding the need for randomized trials, in 2007124 and in 2009.125
Two trials have been completed. The MIST study in patients with a
PFO and migraine, published in 2008,126 and the CLOSURE-1 study
in patients with a PFO and cryptogenic stroke,127 reported in
2010128 but not yet published, both found PFO closure to be no
better than medical treatment. Unfortunately, the procedure is
already so ‘established’ that many clinicians remain unconvinced.129 – 131 No PFO closure device has been approved in the
USA, but many devices continue to be implanted in Europe; a
recent report from a single centre included 825 patients.132
The case for reform
Clinical problems relating to failures of medical devices have led to
mounting concerns over shortcomings in regulatory processes and
calls for their reform, both in Europe and in North America.133 – 143
Most detailed studies have been performed in the USA; for
example, more class III devices are approved by the FDA on
510(k) exemptions than by full clinical evaluation,136 only 27% of
clinical studies used to support premarket applications for cardiovascular devices were randomized,135 and most devices which are
recalled had been approved without detailed evaluation.142 Unfortunately, the lack of information from the many competent authorities and NBs means that no comparable analyses are available
for Europe. Nonetheless, several major issues can be identified.
(1) Complexity of the legislative framework
The main Directives of the EU have been amended several times
and supplemented by various implementing measures and interpretative documents. It is difficult for inexpert health-care professionals to understand fully this large body of texts. Algorithms
can be used to determine the probable class of a device13 but
there is no website that can be visited to confirm how a particular
medical device has been classified or to review the evidence on
which it has been approved. There are substantial variations
between the transposition measures and additional requirements
that some Member States have adopted4 because of the lack of
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Clinical evaluation of cardiovascular devices
Table 2
devices
Extracts from European and international recommendations concerning the clinical evaluation of medical
European Commission Directive
90/385/EEC;
Annexes 1 and 7
The purpose of clinical investigation is to verify that, under normal conditions of use, the
performances of the device comply with those . . . intended by the manufacturer . . . in such a
way that their use does not compromise the clinical condition or safety of patients5
NB-MED/2.7/Rec3; Evaluation of clinical data;
Section 4.1
The manufacturer is required by the Directive to perform a risk analysis . . . . From the results of
the risk analysis, the manufacturer lays out how each risk is addressed and decides on the
acceptability of risks when weighed against the intended benefits145
European Commission MEDDEV 2.7.1;
Annex X, Section 1.1
The objectives of a clinical investigation must be to verify a positive benefit/risk profile of the
device for the indications and limitations of use as specified by the manufacturer10
Global Harmonization Task Force (2010);
Study Group 5; Clinical investigations
Clinical investigations are necessary to provide the data not available through other sources (such
as literature or preclinical testing) required to demonstrate compliance with the relevant
Essential Principles (including safety, clinical performance and acceptability of risk/benefit ratio
associated with its use)24
ISO 14971 (2007); Medical devices—application
of risk management to medical devices
This International Standard specifies a process through which the manufacturer of a medical
device can identify hazards associated with a medical device, estimate and evaluate the risks
associated with these hazards, control these risks, and monitor the effectiveness of that control
For each risk management plan the manufacturer should choose appropriate risk acceptability
criteria27
The clinical evaluation includes an assessment and analysis of clinical data concerning safety or
performance of the investigational device . . . . The evaluation shall be relevant to the intended
purpose of the investigational device and the proposed method of use. It shall be designed . . . to
ensure that the results . . . have clinical relevance and scientific validity28
ISO 14155 (2011); Clinical investigation of medical
devices for human subjects—good clinical practice
detailed guidance at the EU level. The current system is criticized
because there is reputed to be insufficient standardization and uniformity of performance across the NBs. There is no convincing
clinical or public health argument why class III devices should be
regulated in Europe by a fragmented system when a unified
system is used to evaluate drugs.
(2) Regulatory gaps and need to clarify boundaries
Some new technologies are not regulated by the existing texts.
Examples include electronic medical records (currently the
object of a European concerted action to ensure inter-operability
between Member States), software tools for supporting clinical
decisions, and automated methods of quantifying diagnostic
imaging. Inadequate security of a computerized database, a software malfunction, or an erroneous measurement could all have
adverse clinical consequences for an individual patient. Incorporation of medical devices into IT networks in the clinical environment has been recognized as a less regulated area, and so a new
standard has been developed.144 It is sometimes unclear which
devices fall under which directive; special measures are required
for devices that have both mechanical, and biological or pharmaceutical, components (‘borderline’ products).
There appears to be overlap and therefore some imprecision
about the responsibilities of NBs, competent authorities, and
health technology assessment: all three can consider clinical
evidence.
(3) Weakness of the clinical data requirements
The European guidance that is available about the clinical evaluation of medical devices, mostly concerns good clinical practices
and the methodology of clinical trials—in other words, it is
rather vague (Table 2). New ISO standards specify in detail how
clinical studies of devices should be performed,28 but they do
not specify the possibly more important question of when they
are required. The GHTF Study Group 5 has stipulated that
human clinical trials should address residual safety concerns that
cannot be resolved through pre-clinical testing or by evaluating
existing clinical data. Specific criteria including standards applied
by the NBs are not readily available and particular essential
requirements for the clinical evaluation of individual types of
devices are not published in EU guidance. Thus it is often
unclear when there is a need for observational or randomized
clinical studies, and decisions may be inconsistent. In most cases,
it seems to be left to the manufacturer to evaluate potential
risks and decide which clinical data will be sufficient for an application to a NB for CE marking (see Table 2). There is overuse
of equivalence as the basis for approval,57 for example when a
non-inferiority clinical trial with good statistical power has not
been performed.
Medical devices often undergo serial changes, appropriately, as
manufacturing processes evolve and the device is refined or new
facilities and tools are added. Such step-by-step ‘iterative’
changes are offered by the device companies as minor modifications and they may be approved without repeating the process
of clinical or regulatory evaluation. At some point, however, a
sequence of iterative changes must represent a real change in
the device and re-evaluation may be clinically important.
It has been argued that registry studies conducted for the
further clinical evaluation of diagnostic and therapeutic devices
after regulatory approval has been obtained, are the main
control point for medical devices.146 In general, these studies
have been conducted by industry. The manufacturer designs a
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plan for PMS and proposes this to its NB; if the manufacturer then
also selects the participating centres, there is a significant risk of
bias. New methods for automatically monitoring large registries
can identify even low-frequency risks.147,148
(4) Accountability of the Notified Bodies
Given the large number of NBs, it may be difficult to ensure that
they have comparable and high levels of specialist expertise, but
this is desirable for all NBs that review clinical data produced by
manufacturers in order to assess conformity of class III devices.
The claims for a device made by its manufacturer and the evaluation of any particular device by any particular NB are not publicly
available. If approval of a new device has been granted on the basis
of equivalence, it is not reported which data the manufacturer submitted in order to demonstrate that its new device performs the
same task as other devices which have previously been given a certificate and CE mark. It is inappropriate that responsibility for
approving PMS belongs to the NBs rather than the competent
authorities; the complexity and largely sporadic nature of communications regarding FSCAs makes this unsatisfactory. When a
NB receives fees from companies whose devices it assesses,
there may be a conflict of interest.
There is no publicly available list of medical devices in Europe.
Each NB or competent authority may have its own list but there
is currently no formal system for these lists to be shared or for
them to be made available for consultation by patients or healthcare professionals.
(5) Insufficient use of expert medical advice
Concerns have been expressed that there is dialogue between
manufacturers and regulatory authorities but academic clinicians
are rarely involved.149 The organizations responsible for setting
standards, such as CENELEC and IEC, use a large network of
experts, but their activities are supported and partly funded by
industry. National competent authorities and NBs have their
own advisers. The Medical Devices Unit of the EC takes advice
from trade organizations, and individual scientists and clinical
researchers serve as members of its scientific committee. No partnerships have yet been established with professional medical
associations at a European level, but the EC is open to participation
by all stakeholders. The EC is not involved in individual clinical
evaluations or approvals of particular devices (which are the
responsibility of member states and NBs) and so there is no coordinated system for obtaining detailed professional advice concerning new high-risk devices.
Balancing innovation and
regulation
One of the three main objectives of the strategy for health of the
EU from 2008 to 2013 (published by the EC as a white paper in
2007) is to support new technologies ‘which have the potential
to revolutionise healthcare and health systems’. 35 Eighty per
cent of the companies in the medical device sector in the EU
are small and medium enterprises (SMEs)2 and so encouraging
the growth of this sector has been a foremost objective of the
A.G. Fraser et al.
EC, particularly when the Medical Devices Unit was part of DG
ENTR. The health strategy also states, however, that new technologies ‘must be evaluated properly, including for cost-effectiveness
and equity’ and it affirms as a fundamental principle that ‘health
policy must be based on the best scientific evidence derived
from sound data and information, and relevant research.’ For
medical devices, it is not clear that this happens at the EU level.
A key initiative of the Europe 2020 Strategy announced by the
EC in 2010 is the ‘Innovation Union’. One important objective is
to promote research and development of new medicines, treatments, and diagnostic tools to improve quality of life for the
elderly.150 The document includes a general proposal to remove
barriers to bring ideas to market, but concerning the objective
of healthy ageing there are also specific statements relating to
the need to improve rules for clinical trials and testing of new
medicines by the EMA, and to ensure interoperability and the
setting of standards and reference specifications for new
equipment.
Reconciling these priorities—economic sustainability and clinical
scrutiny—will be a key challenge for the planned recast of the
European medical device directives. Two seemingly conflicting
objectives—to streamline and to enhance the legislation—were
recognized in the public consultation that the Commission initiated
in 2008 to seek advice from expert groups and ‘stakeholders’ on
topics such as the clinical evaluation of devices, vigilance, market
surveillance, and transparency.151 The 92 replies from industry
almost unanimously rejected the proposal to expand the role of
EMA in order to create a new European medical devices agency,
whereas there was considerable support for this concept in 41
replies from professional associations, academics, and patients.152
The argument is made, usually by industry, that tighter requirements for clinical testing of devices before approval would stifle
innovation and delay the availability to clinicians of useful new
tools for diagnosing or treating their patients. This ignores the
fact that some innovations are led by advances in technology (‘solutions seeking applications’) rather than being produced in
response to identified clinical needs. Many physicians—for
example, interventional cardiologists—also want to have early
access to new devices and think that medical progress would be
compromized and their patients might be disadvantaged if regulatory approval would take longer, but being at the forefront of technological advances also implies responsibilities to ensure that new
treatments are safe and effective.
The typical product cycle of a medical device is much shorter
than for a drug. The clinical value of an implantable or diagnostic
device may be influenced by other factors, such as the expertise
of the operator. It is reasonable that regulatory systems should
reflect these differences. Classical clinical trials are not always
possible or appropriate, but public health safety must always be
assured by studies to establish a favourable risk/benefit ratio.
Support for innovation153,140 in appropriate cases could be counterbalanced by more rigorous PMS.
A premature conclusion that a device is effective can result in
more harm than good, whereas a premature decision that a
device is ineffective may deprive patients of useful treatment. If
there is any ‘residual safety concern’ then further clinical evaluation
should always be the priority.
Clinical evaluation of cardiovascular devices
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Figure 2 Recommended structure for approving and monitoring medical devices, based on a single European agency overseeing detailed
European standards, assessed by a technical division or by a small number of coordinated Notified Bodies who award a medical CE mark, followed by integrated health technology assessment and post-marketing surveillance. Clinical experts from professional medical associations
should contribute at many stages, as exemplified by the ESC logo.
Recommendations
The Policy Conference strongly supported the plan for a substantial recast of the Device Directives. This is an opportunity to
reconsider the optimal governance of medical devices, going
back to basic principles. It is essential that evidence of clinical efficacy as well as safety and technical performance is established
before approval of any devices whose use may be associated
with more than trivial risks.
(1) There should be a single, coordinated European
system to oversee the evaluation and approval of medical
devices
There should be integration and harmonization of processes
between the competent authorities so that they apply uniform
and higher standards. The most efficient way to achieve this
would be the creation of a single regulatory authority in the EU
(Figure 2); it could be a medical devices division of EMA or a
new body, but its structure is less important than its function.
There should be close collaboration between agencies conducting
PMS and those responsible for health technology assessment, as
well as increased international collaboration.
(2) The NBs should be reorganized as an integrated
structure
The NBs should be reformed, with expertise concerning particular
types of devices concentrated in single centres (for uncommon,
high-risk devices) or only a few centres (for large categories).
The regulatory authorities should direct applications for assessment of devices to the appropriate specialist NB(s). There
should be closer supervision and coordination of the NBs to
ensure that they have a single, high standard of excellence, experience, and competence. Options would be for the divisions of NBs
that assess medical devices to become the technical division of a
new European medical devices agency, or they could remain
decentralized while operating within an integrated system.
The use of the CE mark for medical devices should be reviewed
as its meaning is often misunderstood. It may be interpreted by
clinicians and patients as meaning that clinical effectiveness has
been established, for example from clinical trials, whereas it
simply implies conformity with essential requirements including
an acceptable risk/benefit ratio. For implantable devices, a modified
system should be considered, that indicates the level of clinical evidence established by trials.
(3) The classification of each type of device should be
based on a detailed evaluation of risks
A risk-based classification is essential. This is the foundation of the
current system of regulatory approval, but not all devices within
each class have similar levels of clinical risk. Actual risks should
be reflected in the clinical evidence required for a submission.
For example, diagnostic imaging devices which use ionizing radiation or contrast agents have increased risks compared with safe
alternatives such as ultrasound. The class of each new device
should be considered separately and not determined by the manufacturer. International concordance of classifications is important.
Risk will be influenced by the population in which a device is
used and so clinical indications should be considered when risk
is being estimated. The system should be adaptable so that new
devices can be considered promptly when they are introduced,
before their long-term risks can be known. Also, the system
should not restrict the application of devices in special groups
such as children, when the devices meet technical standards but
limited numbers of patients might make it difficult ever to collect
detailed information about risks.
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Risk assessments should be undertaken for health information
technology.
(4) Product standards should be developed for each
category of medical device in class II and class III
There is a need for specific standards concerning not just the technical design and performance but also the clinical performance and
evaluation and requirements for PMS, of each type of device in
class II and class III. Where these do not already exist, they
should be developed, perhaps on an international basis. Recommendations should include requirements for clinical evaluation
including numbers of patients to be studied, and guidance when
clinical trials are needed to demonstrate an impact on clinical outcomes. These requirements should be binding on manufacturers.
The design of trials may vary according to the class of a device,
risk/benefit ratios, and the characteristics of the patients in
whom it is used. There should be fewer approvals of new
‘me-too’ devices on the basis of equivalence, and standards
should define when this would be acceptable. Approval for the
use of a device should include a statement of its clinical indications.
Clinical evaluation should be extended to diagnostic imaging.
Standards should determine acceptable limits of performance
against imaging phantoms (test objects) and when feasible, acceptable levels of diagnostic accuracy.
Standards should be produced independently, without involvement by the organizations responsible for assessing conformity
of devices. Manufacturers or members of trade associations can
advise or participate as technical experts but they should not
have responsibility for writing or approving standards. The EU or
national competent authorities should fund the production of
detailed standards.
(5) Expert professional advice is required
Professional associations such as the European Society of Cardiology are key stakeholders in developing policy concerning medical
devices, as they represent networks of physicians who develop,
use, and evaluate devices in daily clinical practice, and who understand and practise different methods of clinical assessment. Obtaining expert advice, for example from (bio)materials scientists,
physicists, engineers, academic specialists, practising physicians,
and nurses, should be an integral part of the regulatory process.
Such independent advisers should be involved in setting standards,
reviewing decisions about approval of new class III devices, defining
clinical indications, performing health technology assessment, and
designing and conducting programmes for PMS (Figure 2). Representatives with appropriate training and experience should be
nominated by major medical associations in Europe to be
members of the main advisory committees.
It is important that the experience and opinions of patients who
use devices or who have received implantable devices should also
be obtained and considered.
(6) Adequate transparency is essential
Legislation enacted by the European Parliament in 2001 on
freedom of information enshrined the right of access of European
citizens to documents of the EC and its agencies.154 There are
A.G. Fraser et al.
compelling clinical reasons why transparency should be extended
to documents relating to the approval of medical devices.
Currently, it is difficult for physicians to identify the class of any
particular device or to obtain its essential requirements as evaluated by the NBs. Technical standards such as those produced by
ISO can only be consulted by purchasing the documents. For
medical devices, such information should be freely available in
the public domain.
The content of dossiers prepared by companies when submitting their devices for approval, apart from any manufacturing
details that are protected intellectual property, should be disclosed
to physicians so that they can know the technical performance of
the devices that they use. They should be able to review comparisons of the performance of devices within the same category.
Patients should be able to obtain information such as reports of
malfunctioning devices, preferably together with professional
advice from physicians.155
(7) The concept of conditional approval of a medical
device, pending further clinical evaluation, should be
developed
When a new device is developed that represents a major technical
advance and an important new option for treatment, then early
approval may be appropriate as long as initial clinical safety and efficacy have been established and the clinical benefits from its use are
likely to outweigh any anticipated risks. There would still be a need,
however, for larger, longer, or randomized clinical studies to be
performed. In such circumstances, CE marking might be awarded
for a limited period (such as 2 or 3 years), conditional on the manufacturer reporting back to the regulatory authority before the
expiry of that time period with the results of any further clinical
studies that have been specified as the condition of approval. If
new evidence is not submitted, then permission for continued
marketing of the device would be withdrawn. The new category
could be called ‘Conditional Approval of a Device, pending clinical
trial’. For diagnostic imaging, a similar concept has been described
as ‘coverage with evidence development’.156 This proposal is not
the same as an IDE, because the device could be CE marked
while the manufacturer is mandated to undertake specific clinical
research studies in addition to PMS.
The current directives already allow for compassionate use and
investigational device approval, but this is granted by a national
competent authority and not at the European level.
(8) Outcome studies after device implantation should be
undertaken as a partnership between physicians,
companies, and regulators
Post-marketing surveillance should be initiated by the manufacturer but PMS should not be the sole responsibility of industry.
Follow-up studies should be proposed and coordinated by regulatory agencies or HTA bodies with the assistance of independent
experts from professional scientific associations (such as the
ESC155). Funding for such studies might vary, from manufacturers
to the EU itself, depending on the scope of information being gathered and its relevance to a specific device or to public health.
These studies should evaluate the characteristics of patients undergoing diagnostic or therapeutic procedures using devices including
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Clinical evaluation of cardiovascular devices
off-label applications, document immediate complications, and
study medium and long-term outcomes including instances of
device failure. To ensure that data are representative, outcomes
should be collected from centres in all Member States that
reflect different types and volumes of practice and the full range
of complexity of clinical cases. Protocols and case record forms
(CRFs) should be discussed and validated by academic experts,
regulators, and companies. The database should not be the property of industry, and the main results should be freely available. A
collaboration between EU regulatory bodies, the FDA, and scientific associations would allow coordination of reporting systems
and more complete evaluation of safety issues related to newly
marketed devices. This will complement the sharing of reports
of adverse events and clinical alerts that is being developed by
Eudamed.
(9) Limits to iterative changes should be defined
Detailed standards for each type of device should specify which
modifications could reasonably be described as minor, and which
others would warrant complete resubmission for approval as a
new device. For example, if any modification has been submitted
for a new patent, or if the materials used to make a device have
been changed, then a de novo application should be required.
(10) Regulatory systems should retain flexibility for special
circumstances
The system of regulatory approval should allow prototype or innovative devices to be approved for use in special circumstances
when urgent clinical needs can only be met by their deployment.
A common European equivalent of the HDE is required.
Special consideration might also be given to categories of
medical device that are important but used so infrequently that
they are not economically viable. Continuing clinical availability of
‘orphan devices’ might be supported by a grant from a common
fund—for example, if a device is ‘last in class’.
It may be difficult for devices used in paediatric cardiology to
meet the standards and levels of clinical evidence required for
devices used in adults, if numbers of patients are small or if
devices are customized for each patient. Off-label use is
common. Approval on the basis of limited evidence might then
need to be balanced by more strict requirements for careful and
complete PMS.157
(11) Manufacturers should be responsible for the clinical
evaluation of all class II and class III devices
Companies that manufacture any class II or class III devices should
be responsible for initiating independently monitored clinical
studies of their devices, including randomized controlled trials
when these are required according to new standards, and also
for supporting PMS. Researchers should have full access to the
results of any clinical study so that they can conduct an independent statistical analysis, and the results should be published
whether they are negative or positive. Clinical trials evaluating
medical devices should be registered in a central database.158
Depending on the class of device, companies should also train
medical and nursing staff in the correct and safe use of their
devices.
(12) Physicians should understand and engage with the
regulatory systems for medical devices
Physicians have a responsibility to practice evidence-based medicine when using devices, and they should encourage their patients
to participate in clinical trials when these are required, especially
when there is equipoise. Physicians are keen to adopt new
devices early but not as keen to undertake systematic monitoring
afterwards; they should contribute routinely to PMS as this may be
the only means by which unsuspected problems are discovered. It
is the duty of physicians to report any failure of a device. Consideration could be given in the case of high-risk devices to making participation in PMS mandatory, as a requirement either for continued
access to the device for their patients or to reimbursement of the
hospital for its use. Professional societies should promote interest
in the evaluation of innovative medical devices, through continuing
medical education.
It is unethical for any physician to accept payment from a
medical device company for the use of its device. If physicians
have any financial interest in a device, they should disclose this
information when reporting its performance or seeking consent
for its use.
Conflict of interest: A.G.F. acknowledges support to his
institution for research from Hitachi-Aloka and GE Ultrasound.
J-C.D. is a consultant and member of the speakers’ bureaux for
EBR Systems Inc, Medtronic, Sorin, and St Jude Medical. N.A.M.
receives modest consulting fees from Boston Scientific, and
Medtronic. M.W.K. is a special government employee of the
FDA. P.E.V. is a consultant for Medtronic and has received
support to his institution for research from St Jude Medical.
F.VdW, S.C.S, and M.K. have no conflicts of interest related to
this article.
Appendix
Participants in Policy Conference
Stefan Anker, President Elect of the Heart Failure Association of
the ESC, Charité Hospital Berlin, Germany. Angelo Auricchio, President Elect of the European Heart Rhythm Association, Fondazione Cardiocentro Ticino, Switzerland. Steven Bailey, Past
President of the Society of Cardiac Angiography and Interventions,
Health Science Center, San Antonio, TX, USA. Philipp Bonhoeffer,
Institute of Child Health, University College London, UK. Martin
Borggrefe, Councillor, ESC, Universitätsmedizin Mannheim,
Germany. Lars-Åke Brodin, Professor of Medical Engineering and
Dean, School of Technology and Health, Royal Institute of Technology, Stockholm, Sweden. Nico Bruining, Past Chairman, ESC
Working Group on Computers in Cardiology, Erasmus Medical
Center-Thoraxcentre, Rotterdam, Netherlands. Peter Buser, ESC
Council on Cardiovascular Imaging, University Hospital, Basel,
Switzerland. Eric Butchart, Past Chairman, ESC Working Group
on Valvular Heart Disease, University Hospital of Wales, Cardiff,
UK. Jose Calle Gordo, Chairman Cardiovascular Sector,
EUCOMED, Brussels, Belgium. John Cleland, Past President,
Heart Failure Association of the ESC, University of Hull, UK.
Nicolas Danchin, European Affairs Committee, ESC, Hôpital
1686
Européen Georges Pompidou, Paris, France. J.-C.D., European
Affairs Committee, ESC, C.H.R.U. de Pontchaillou, Rennes,
France. Muzaffer Degertekin, Councillor, European Society of
Cardiology, Yeditepe University Hospital, Istanbul, Turkey. Isabelle
Demade, Medical Devices Unit, DG SANCO, European Commission, Brussels, Belgium. Nicole Denjoy, Secretary General, COCIR,
Brussels, Belgium. Geneviève Derumeaux, Councillor, ESC, President, French Society of Cardiology, Hôpital Louis Pradel, Lyon,
France. Carlo di Mario, President of the European Association of
Percutaneous Coronary Interventions, Royal Brompton Hospital,
London, UK. Kenneth Dickstein, Past-President, Heart Failure
Association of the ESC, Stavanger University Hospital, Stavanger,
Norway. Dariusz Dudek, European Association of Percutaneous
Coronary Interventions, Institute of Cardiology, Krakow, Poland.
M.E., American Heart Association, Tufts University School of
Medicine, Boston, MA, USA. Andrew Farb, Center for Devices
and Radiological Health, Food and Drug Administration, Silver
Spring, MD, USA. Albert Flotats, Chairperson, Cardiovascular
Committee, European Association of Nuclear Medicine, Hospital
Sant Pau, Barcelona, Spain. A.G.F., Past-President, European
Association of Echocardiography, Wales Heart Research Institute,
Cardiff University, UK. Pascal Gueret, European Association of
Echocardiography, Henri Mondor University Hospital, Creteil,
France. Carsten Israel, European Heart Rhythm Association, Evangelisches Krankenhaus Bielefeld, Germany. Stefan James, Chairman,
Databases and Registries, European Association of Percutaneous
Coronary Interventions, Uppsala Clinical Research Centre,
Sweden. Josef Kautzner, Councillor, ESC, Institute for Clinical
and Experimental Medicine, Prague, Czech Republic. M.K., President of the ESC, CHU Pitié Salpêtrière, Paris, France. M.W.K.,
American College of Cardiology, Duke Clinical Research Institute/Duke University Medical Center, Durham, NC, USA.
Massimo Lombardi, Past-Chairman, ESC Working Group on
Cardiovascular Magnetic Resonance, CNR—National Research
Council, Pisa, Italy. Tom Marwick, Cleveland Clinic, Cleveland,
OH, USA; Princess Alexandra Hospital, University of Queensland,
Australia. Muriel Mioulet, Director, Advocacy and Representation,
ESC, European Heart House, Sophia Antipolis, France. Sophie
O’Kelly, Head of European Affairs, ESC, European Heart House,
Sophia Antipolis, France. Pasquale Perrone-Filardi, Chairman
Elect, ESC Working Group on Nuclear Cardiology and Cardiac
CT, Universita’ Federico II, Napoli, Italy. Giuseppe Rosano,
IRCCS San Raffaele Hospital, Roma, Italy. Raphael Rosenhek,
Chairman Elect, ESC Working Group on Valvular Heart Disease,
Medical University of Vienna, Austria. Manel Sabate, Board
member, European Association of Percutaneous Coronary Interventions, University of Barcelona, Spain. S.C.S., Jr, President of
the World Heart Federation, Geneva, Switzerland; Professor of
Medicine, University of North Carolina, Chapel Hill NC, USA.
Eva Swahn, Vice President of the ESC, Linköping Heart Centre,
Sweden. Luigi Tavazzi, Chairman, EurObservational Research Programme of the ESC, Gvm Care & Research, Cotignola, Italy. F.W.,
Chairman, European Affairs Committee of the ESC, Catholic University Leuven, Belgium. Enno van der Velde, Chairman, ESC
Working Group on Computers in Cardiology, Leiden University
Medical Center, Leiden, Netherlands. Lex van Herwerden,
Professor of Cardiac Surgery, University Medical Center Utrecht,
A.G. Fraser et al.
Netherlands. P.E.V., President Elect of the ESC, Heraklion University Hospital, Greece. Jens-Uwe Voigt, Chairman, Education
Committee, European Association of Echocardiography, Catholic
University Leuven, Belgium. Douglas Weaver, Past President of
the American College of Cardiology, Henry Ford Hospital,
Detroit, MI, USA. Peter Wilmshurst, Consultant Cardiologist,
Royal Shrewesbury Hospital, UK. Disclosures of interests
of participants are available from the European Society of
Cardiology.
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